Natural age related declines in testosterone (T) are associated with decrements in cognitive abilities independent of health status. Low T levels over time are associated with increased risk for developing Alzheimer's disease (AD). These findings suggest that men with low T levels are most at risk for age-related cognitive decline and AD and therefore most likely to benefit from T supplementation to prevent the development of AD or age-associated cognitive decline. Studies in our laboratory as well as others provide support that both hypogonadal and eugonadal men, and men demonstrate cognitive improvements from T supplementation for brief treatment periods (6-12 weeks), when assessed at a supraphysiological or peak level. It is unknown whether T supplementation over a longer treatment period (6 months) or using a percutaneous formulation that provides a steady state, physiological dose level will result in beneficial cognitive changes in older men at risk for further cognitive decline from either mild cognitive impairment (MCI) and/or low T levels. In addition to behavioral changes, T may reduce further cognitive decline due to effects on pathophysiological biomarkers such as beta-amyloid (Aft) 1-40, 42 and tau which are thought to be related to onset and disease progression in AD. Both animal and human studies indicate that plasma and brain levels of AR.40, 42 are androgen responsive. Androgens may also have a role in modulating AD onset and progression in MCI individuals due to interactions with apolipoprotein E*4 (APOE*4) as androgens protect against the cognitive declines observed in transgenic APOE mice. The proposed study will examine cognitive, mood and cerebrospinal fluid (CSF) biomarker response to T supplementation in older men with mild cognitive impairment (MCI) and low serum T levels. The proposed study builds on our previous findings by examining cognitive response over a longer period of time (6 months) and assess whether these cognitive changes are observed within a physiologic range, and steady state dose level achieved using a new percutaneous gel preparation. This project is a novel area of inquiry that fits the goals and criteria of PAR-05-021 for pilot clinical trials directed toward the prevention and treatment of age-associated cognitive decline and Alzheimer's disease (AD). Given that the incidence of older men with low T levels increases with age as does the risk for MCI and AD, the public health implications of a potential therapeutic intervention in this population are tremendous. A therapeutic benefit of T supplementation may provide another possible treatment alternative and/or one that can be combined with existing medications. Further, results of this study will provide valuable information for planning, larger future trials of T supplementation or selective androgen receptor modulators (SARMs). [unreadable] [unreadable] [unreadable]